Process for the preparation of 3,7-dialkylxanthines

ABSTRACT

The invention is directed to a process for preparing 3,7-dialkylxanthines of the formula I ##STR1## (R 1  and R 2  denote C 1  -C 4  -alkyl) by the reaction of 4-amino-imidazolecarboxamide-(5) of the formula II ##STR2## with an alkali cyanate in aqueous solution at a pH of from 3 to 5 followed by cyclization of the resulting urea derivative at a pH of from 8 to 14.

DESCRIPTION

The present invention relates to a novel process for the preparation of3,7-dialkylxanthines of the general formula I ##STR3## in which R¹ andR² denote C₁ -C₄ -alkyl.

Hitherto, 3,7-dialkylxanthines have only been obtainable by expensivetotal synthese or by isolation from vegetable products such as cocoabeans or tea waste products. An exception is the partial snythesis oftheobromine (3,7-dimethylxanthine) proposed by H. Biltz et al., [Chem.Ber. (1931), Vol. 64, page 1970], in which hydrogen chloride is passed,at 160° C., through a melt of caffeidine and methyl or ethyl urea. Thisprocess suffers from the drawbacks that the highly corrosive melt isdifficult to handle and purification of the theobromine is an expensiveprocedure. A further disclosure from the work of H. Biltz et al., [Chem.Ber. (1928). Vol. 61, 1409] is the reaction of caffeidine with potassiumcyanate in aqueous solution to produce caffeine. According to theexperimental data, this reaction takes place in a weakly acid to neutralmedium at a pH of from 5.5 to 7.5.

It is an object of the present invention to provide novel processes forthe preparation of 3,7-dialkylxanthines.

Accordingly, we have found a process for the preparation of3,7-dialkylxanthines of the general formula I ##STR4## in which R¹ andR² denote C₁ -C₄ -alkyl, wherein a1-alkyl-4-alkylamino-5-alkylaminocarbonylimidazole of the generalformula II ##STR5## in which R³ denotes C₁ -C₄ -alkyl, is reacted withan alkali metal cyanate in aqueous solution at a pH of from 3 to 5, andthe resulting urea derivative is subjected to cyclization at a pH offrom 8 to 14 to form the corresponding 3,7-dialkylxanthines (I).

The fact that this reaction effects cleavage of the amine R³ --NH₂ must,in view of the paper by H. Blitz et al. on caffeine synthesis (loc.cit.), be regarded as a surprising feature.

The starting materials II, of which caffeidine (R¹, R² and R³ denotemethyl) is the most significant, are known or can be prepared by knownmethods. They are preferably prepared by alkaline hydrolysis of thecorresponding 1,3,7-trialkylxanthines III ##STR6##

Other important starting materials are those in which R¹ and R² denoteethyl or isopropyl groups.

In the process of the invention, the aqueous solutions of the compoundsII are adjusted to a pH of from 3 to 5 with an acid.

Examples of suitable acids are mineral acids such as hydrochloric acid,sulfuric acid and phosphoric acid, or organic acids such as acetic acid,formic acid and oxalic acid, and since the reaction is pH-sensitive,buffer systems may be used to maintain specific pH's, examples beingsodium acetate/acetic acid or sodium dihydrogen phosphate/disodiumhydrogen phosphate.

In the preparation of theobromine, yields of more than 60% are obtainedin a pH range of from 4.3 to 4.7. When using a caffeidine homologue asstarting material, the optimum pH range can be readily determined bycarrying out preliminary tests.

Preferredalkali metal cyanates are sodium cyanate and potassium cyanateused in a concentration of from 1 to 4 moles and preferably from 1 to 2moles, per mole of II. A greater excess of alkali metal cyantate ispossible, but not necessary. The concentration of compound II in theaqueous solution is not critical and is usually in the range of from 0.2to 4 moles per liter. When preparing theobromine, the best results areobtained at a caffeidine concentration of from 0.5 to 2 moles per liter.The reaction proceeds satisfactorily at from 0° to 50° C. The use ofhigher temperatures is possible, but this leads to an increasedconsumption of alkali metal cyanate.

The resulting urea derivative IV ##STR7## can be isolated or convertedto 3,7-dialkylxanthines in situ. Cyclization to compounds I is effectedin an alkaline medium at elevated temperature. A pH ranging from 11 to13 is particularly preferred, whilst a value of from 11.6 to 12.0 is tobe partically recommended for the preparation of theobromine.

The 3,7-dialkylxanthines can be isolated by adjusting the pH to theisoelectric point to effect precipitation, followed by filtration andextraction with a suitable solvent. The end products, particularlytheobromine and its derivatives, are known to be pharmacological agentsof considerable importance.

EXAMPLE

A solution of 84 g (0.5 mole) of caffeidine in 450 ml of water wasadjusted to pH 4.5 with glacial acetic acid, and 41.6 g (0.66 mole) ofsodium cyanate were added portionwise thereto over a period of 4.5 hoursat 25° C. After standing for 12 hours, the precipitated solids wereredissolved in 100 ml of water, and the solution was adjusted to pH 11.8with 100 ml of a 50% caustic soda solution. The reaction solution wasthen heated at the boil for 1.5 hours.

The product was isolated by adjusting the solution to pH 6.1 withglacial acetic acid. Theobromine precipitated on cooling. Thetheobromine was filtered off, washed with water and a little acetone andonce again with hot water.

Yield: 62.8% M.p. 350° C.

We claim:
 1. A process for the preparation of a 3,7-dialkylxanthine ofthe formula I ##STR8## in which R¹ and R² denote C₁ -C₄ -alkyl, whereina 1-alkyl-4-alkylamino-5-alkylaminocarbonylimidazole of the formula II##STR9## in which R³ denotes C₁ -C₄ -alkyl, is reacted with an alkalimetal cyanate in aqueous solution at a pH of from 3 to 5, and theresulting urea derivative is subjected to cyclization at a pH of from 8to 14 to form the corresponding 3,7-dialkylxanthine (I).